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Vol. 31, Issue 3, 282-288, March 2003

Induction of Cytochrome P450 Enzymes in Cultured Precision-Cut Human Liver Slices

Robert J. Edwards, Roger J. Price, Patricia S. Watts, Anthony B. Renwick, J. Michael Tredger, Alan R. Boobis, and Brian G. Lake

BIBRA International Ltd., Carshalton, Surrey (R.J.P, A.B.R, B.G.L.); Section on Clinical Pharmacology, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London (R.J.E., P.S.W., A.R.B.); and Institute of Liver Studies, Guy's, King's and St. Thomas' School of Medicine, London, United Kingdom (J.M.T.)

Precision-cut human liver slices obtained from 11 donors were cultured for 72 h in a defined medium (serum free Williams' medium E) supplemented with 0.1 µM insulin and 0.1 µM dexamethasone (DEX). Liver slices were treated with 50 µM concentrations of beta  -naphthoflavone (BNF), lansoprazole, rifampicin (RIF), DEX and methylclofenapate and 500 µM sodium phenobarbital (NaPB). The relative apoprotein levels of 12 cytochrome P450 (P450) enzymes were determined in liver slice microsomes using a panel of antipeptide antibodies. Treatment with BNF significantly induced mean levels of CYP1A2 apoprotein to 160% of levels in 72-h control (no test compound) human liver slice microsomes. NaPB significantly induced levels of CYP3A4 apoprotein to 255% of control and RIF significantly induced levels of CYP2C19 and CYP3A4 apoproteins to 265 and 330% of control, respectively. In addition, treatment with RIF increased levels of CYP2A6 apoprotein to 205% of control, and treatment with both NaPB and RIF increased levels of CYP2B6 apoprotein to 370 and 615% of control, respectively. However, these increases were not statistically significant, owing to a variable response between liver slice preparations from different subjects, this being apparent for all inducible P450s. In contrast, none of the compounds examined significantly increased levels of CYP2C8, CYP2C9, CYP2D6, CYP2E1, and CYP4A11 apoproteins. Levels of CYP1A1 apoprotein were not detected in any liver slice sample, either before or after treatment with the model inducers. Overall, these results demonstrate the utility of cultured human liver slices for assessing the effects of chemicals on P450 enzymes.

Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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